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Funding Acknowledgements Type of funding sources: None. Background Novel radiofrequency (RF) ablation technology permits local impedance (LI) assessment, enabling increased knowledge of the underlying tissue’s properties. In addition, LI can provide details on catheter tip contact and extent/effectiveness of radiofrequency (RF) delivery. To date, the extent to which left atrial (LA) tissue characterization by LI can guide RF ablation has not yet been explored. Purpose We aimed to assess LI capabilities of predicting RF ablation success in consecutive AF cases with different underlying cardiac tissue characteristics. Methods Two-hundred twelve consecutive patients undergoing de novo AF ablation at 16 European centers were included in the CHARISMA registry. A novel ablation catheter (Stablepoint) with dedicated algorithm (DirectSense) was used to measure LI at the distal electrode. Each ablation point was characterized in terms of RF delivery time, baseline LI and LI drop during ablation according to different atrial substrates: normal-voltage (NV, >0.5mV), intermediate-voltage (IV, 0.1-0.5mV) and low-voltage tissue (LV, Results Atrial substrate was analyzed at 11405 (82%) sites with complete high-quality data. Ablation spots were more frequently deployed in NV areas (n=6714, 58.9%) than in areas of IV (n=4065, 35.6%) or LV (n=625, 5.5%). Both baseline LI (163.8±19Ω) and LI drop (23.0±9Ω) were higher in NV areas than in IV areas (baseline LI: 159.4±18Ω, p20Ω for NV areas (Sensitivity=62.5%, Specificity=91.5%, PPV=99.6%, Area under the receiver-operating characteristic curve (AUC)=0.7896, p18Ω for IV and LV areas (Sensitivity=57.7%, Specificity=94.6%, PPV=99.8%, AUC=0.8008, p Conclusion LI drop during ablation significantly differs according to atrial substrates. These findings suggest that a tailored AF ablation strategy taking into account the underling LA substrate may be useful.

Avatrombopag, a thrombopoietin receptor agonist, can reduce the need for platelet transfusions or rescue interventions for bleeding in patients with chronic liver disease (CLD) and thrombocytopenia undergoing scheduled procedures. A model analysis indicated that the effect of avatrombopag on platelet production was reduced in East Asian versus non-East Asian patients; however, the difference was deemed not clinically significant. Furthermore, a subgroup analysis of pooled Phase 3 trials showed similar avatrombopag efficacy across racial subgroups. The aim of this Phase 2 study was to corroborate the efficacy and safety of avatrombopag in Japanese patients with thrombocytopenia due to CLD.Japanese patients with CLD and thrombocytopenia were randomized to receive placebo or avatrombopag 20, 40, or 60 mg daily for 5 days. The primary endpoint was responder rate in platelet counts at Visit 4 (10-13 days after treatment initiation), defined as the proportion of patients with platelet count ≥50 × 10Thirty-nine patients were randomized and completed the study (placebo, n = 11; avatrombopag 20 mg, n = 7; 40 mg, n = 11; 60 mg, n = 10). Avatrombopag treatment was associated with significant increases in responder rate at Visit 4 in the 40 mg (63.6%; p = 0.004) and 60 mg (40%; p = 0.024) groups versus placebo (9.1%). Avatrombopag was well tolerated and no new safety signals were detected.Efficacy and safety results from this study were consistent with previous studies in patients with CLD and thrombocytopenia undergoing elective procedures, supporting treatment with avatrombopag in the Japanese population.gov identifier: NCT02227693.

Histological examination of samples, mC measurement by Mass Spec, survival curves showing the effect of p16Ink4 deletion, qPCR of hmC-related enzymes and melanoma related genes, hmedIP-pcr confirmation of hmedIP-seq, list of primers

Description of supplementary tables and figures

DhmR and gene expression related to Fig1

DhmR and gene expression tet-/- related to Fig3

Although numerous epigenetic aberrancies accumulate in melanoma, their contribution to initiation and progression remain unclear. The epigenetic mark 5-hydroxymethylcytosine (5hmC), generated through TET-mediated DNA modification, is now referred to as the sixth base of DNA and has recently been reported as a potential biomarker for multiple types of cancer. Loss of 5hmC is an epigenetic hallmark of melanoma, but whether a decrease in 5hmc levels contributes directly to pathogenesis or whether it merely results from disease progression–associated epigenetic remodeling remains to be established. Here, we show that NRAS-driven melanomagenesis in mice is accompanied by an overall decrease in 5hmC and specific 5hmC gains in selected gene bodies. Strikingly, genetic ablation of Tet2 in mice cooperated with oncogenic NRASQ61K to promote melanoma initiation while suppressing specific gains in 5hmC. We conclude that TET2 acts as a barrier to melanoma initiation and progression, partly by promoting 5hmC gains in specific gene bodies.Significance:This work emphasizes the importance of epigenome plasticity in cancer development and highlights the involvement of druggable epigenetic factors in cancer.

In mammals, centromeres are epigenetically specified by the histone H3 variant CENP-A and are typically associated with satellite DNA. We previously described the first example of a natural satellite-free centromere on Equus caballus chromosome 11 (ECA11) and, subsequently, on several chromosomes in other species of the genus Equus. We discovered that these satellite-free neocentromeres arose recently during evolution through centromere repositioning and/or chromosomal fusion, after inactivation of the ancestral centromere, where, in many cases, blocks of satellite sequences were maintained. Here, we investigated by FISH the chromosomal distribution of satellite DNA families in Equus przewalskii (EPR), demonstrating a good degree of conservation of the localization of the major horse satellite families 37cen and 2PI with the domestic horse. Moreover, we demonstrated, by ChIP-seq, that 37cen is the satellite bound by CENP-A and that the centromere of EPR10, the ortholog of ECA11, is devoid of satellite sequences. Our results confirm that these two species are closely related and that the event of centromere repositioning which gave rise to EPR10/ECA11 centromeres occurred in the common ancestor, before the separation of the two horse lineages.

Introduction Female patients underrepresentation in clinical trials is a well known issue in clinical research, especially harming the assessment of interventional cardiovascular devices. Limited inclusion of women in such studies might lead to suboptimal care, as results derived from predominantly male populations might not hold true for female patients. In recent years, third generation drug-eluting stents have become the standard of care for percutaneous coronary interventions (PCI). Among them, the Orsiro sirolimus-eluting stent carries some promising features such some of the thinnest struts among commercially available devices (60-80 µm), a bioresorbable-polymer and an amorphous silicon carbide coating. We performed the presents study with the aim to assess if use of this stent in a real-world setting might lead to differential clinical outcomes in women compared to men. Methods This is a retrospective study conducted at a single, high-volume center, including all patients undergoing PCI with the implantation of at least one Orsiro for acute or chronic coronary syndromes between January 2017 and December 2019. Main clinical and procedural features were collected, as well as in hospital outcomes. Follow-up data were collected by outpatient visit or by telephone interview. Target lesion failure (TLF), a composite of cardiovascular death, target vessel myocardial infarction or target lesion revascularization, was the main outcome. Results Out of a total of 416 patients treated with at least an Orsiro stent, 66 (15.9%) were women and 349 (84.1%) men. No significant differences were observed at baseline, excepted for a higher age (median age 70 vs. 66, P=0.003) and a lower BMI (25.0 vs. 26.1, P=0.010) in women compared to men. No gender-related differences were observed in the indication for PCI, with most of the patients presenting with chronic coronary syndrome (329, 79.3%), rather than acute coronary syndrome in (86, 20.7%). The global number of treated lesions was 558 (90 in women, 468 in men); frequency of left main (5.3% vs. 3.0%) and left anterior descending (34.9% vs. 42.4%) PCI was similar (P=0.28). Treated vessels number of treated lesion per patients (1.36 vs. 1.34, P=0.83), cumulative stent length (33.6 mm vs. 38.4, P=0.078) and mean stent diameter (2.92 vs. 3.0 mm, P=0.39) was not different between men and women. Technical and clinical success was achieved in all cases. Two cases (0.5%) of stent thrombosis, one early and one late, were documented, all in men. After a median follow-up of 402 days, the main outcome of TLF was observed in 10 (2.9%) men and 2 (3.0%) women, with no significant differences at log-rank analysis (2.34 events per 100 patient-years in males, 2.53 in females; P=0.80). In the subgroup of patients undergoing small-vessel PCI (stent diameter ≤ 2.5 mm) no differences were observed in terms of TLF at follow-up between women and men (3.2% vs. 4.9%; P = 0.68). Similar findings emerged in the subgroup of patients presenting with acute coronary syndrome (6.3% vs. 4.3%, P = 0.74) Conclusions Ultrathin struts Orsiro stent did not show significant differences in terms of procedural, short-term and long-term outcomes in women compared to men in a real-world setting. This device may represent a viable option for female and male patients undergoing PCI.

Background The objective of this study was to compare the clinical outcomes of patients receiving a short course (SC) vs a prolonged course (PC) of antifungal therapy for uncomplicated Candida bloodstream infections (BSIs). Methods All episodes of uncomplicated Candida BSI from September 1, 2018, to August 31, 2020, were reviewed. We compared the primary (all-cause 90-day mortality) and secondary study end points (1-year recurrent Candida BSI and all-cause 1-year mortality) among patients who underwent SC (5–11 days) or PC (12–24 days) therapy using propensity score analysis with the inverse probability of treatment weighting (IPTW) method. Results A total of 114 patients with uncomplicated Candida BSI were included: 35 (30.7%) were classified into the SC group (median [interquartile range {IQR}], 9 [7–11] days) and 79 (69.3%) into the PC group (median [IQR], 14 [14–16] days). Patients in the SC group compared with the PC group had a higher rate of hospitalization in the surgical ward (40.0% vs 19.0%; P = .02) or septic shock at the time of Candida BSI onset (11.4% vs 1.3%; P = .03). The risk of 90-day mortality was not different between the SC and PC groups (n = 8 [22.9%] vs 17 [21.5%], respectively; IPTW-adjusted subdistribution hazard ratio [sHR], 0.67; 95% CI, 0.31–1.47; P = .20). The risk for recurrent Candida BSI within 1 year of completing therapy (IPTW-adjusted sHR, 1.07; 95% CI, 0.20–5.80; P = .94) or for all-cause 1-year mortality (IPTW-adjusted HR, 0.72; 95% CI, 0.35–1.50; P = .38) did not differ between groups. Conclusions Receiving a short vs prolonged course of antifungal therapy did not affect mortality or BSI recurrence in patients with uncomplicated candidemia.

Recognition of pathogen-associated molecular patterns can trigger the IRE1α arm of the endoplasmic reticulum (ER) stress response in immune cells. IRE1α activation has been shown to maintain ER homeostasis while simultaneously coordinating diverse immunomodulatory programs in the setting of bacterial and viral infections. However, the role of IRE1α signaling in innate immune responses to fungal pathogens is unknown. Here we report that systemic infection with the fungusCandida albicanscauses severe renal immunopathology by triggering inflammatory IRE1α hyperactivation in host myeloid cells. Mechanistically, sensing of fungal β-glucans by the C-type lectin receptor Dectin-1 induced Src–Syk–NOX-dependent accumulation of intracellular reactive oxygen species and the ensuing generation of lipid peroxidation byproducts that sustained IRE1α activation. Selective deletion of IRE1α in leukocytes, or treatment with an IRE1α pharmacological inhibitor, reduced detrimental inflammatory responses in the kidney and extended survival in mice systemically infected withC. albicans. Hence, controlling IRE1α overactivation may be useful to impede the fatal immunopathogenic progression of disseminated candidiasis.One sentence summaryInnate IRE1α signaling in disseminated candidiasis